The present invention is concerned with certain racemic and optically active (2R,4R) hydroxyacetic acid derivatives which are 4-c-hydroxy-2-r-(substituted)-chroman (and thiochroman)-4-acetic acids and pharmaceutically-acceptable salts thereof which, by their inhibition of the aldose reductace enzyme, are useful in the treatment of diabetic complications. It is also concerned with intermediates useful in the synthesis of these compounds.
Compounds, such as sorbinil (S-6-fluorospiro[chroman-4,4'-imidazoline]-2',5'-dione), which have aldose reductase inhibitory activity, are of value in controlling certain chronic complications arising from diabetes mellitus (e.g., diabetic cataracts and neuropathy). The racemic precursor of sorbinil (and analogs thereof) were originally reported by Sarges in U.S. Pat. No. 4,117,230. Sorbinil itself, which is chiral, was first reported by Sarges in U.S. Pat. No. 4,130,714. Its chloro analog (in which 6-chloro replaces 6-fluoro) has also been reported (Sarges, U.S. Pat. No. 4,286,098), as has the 2R-methyl analog of sorbinil (Ueda et al., U.S. Pat. No. 4,540,704).
Non-hydantoin compounds previously reported to inhibit aldose reductase include halogen substituted chroman-4-carboxylic and chroman-4-acetic acids (Belletire, U.S. Pat. No. 4,210,663), and spiro[chroman-4,5'-oxazolidin]-2',3'-diones (Schnur, U.S. Pat. No. 4,200,642).
The chemical nomenclature employed herein is that of the "IUPAC Nomenclature of Organic Chemistry, 1979 Edition," Pergammon Press. Thus, chromans are named as such as permitted under Rule B-2.12 at page 62; thiochromans (in which sulfur replaces the oxygen atom of chroman) are named according to Rule B-4 "replacement nomenclature" at page 68 as 3,4-dihydro-2H-1-thianaphthalenes; racemic cis-trans isomers are named according to Rule E-2.3.4 at page 478 in which c is used as an abbreviation for cis and r is used as an abbreviation for the reference group; and R and S are used to designate chiral carbon atoms according to Rule E-4.9 at 481 and the Sequence Rule at page 486 et seq.